Colorectal carcinoma (CRC) is the fourth most common malignancy worldwide following cancers of the lung, breast and prostate. Metastases of CRC origin are the main cause of death in patients diagnosed with colorectal primary tumours. Approximately 150,000 to 200,000 new cases are diagnosed annually in the USA and around 50,000 deaths are attributed to this disease. Many patients die due to the metastatic spread of the disease with 60-80% of cases developing liver lesions during the illness. The positive identification of liver metastasis is therefore a clear indication of latent disease. Although much less common, other possible sites of spread include lung, brain and occasionally bone.
Due to the strong correlation between extent of liver involvement (number and location of metastasis) and resectability, the appropriate evaluation of patients regarding suitability for surgery is becoming more important (Liver Metastasis: Biology, diagnosis and treatment. Garden O. J., Gereghty J. G., Nagorney D. M. eds. 1998). The need for an agent capable of detecting metastasis of small size (<1 cm) will have a profound impact on the treatment and management of CRC patients. There is a need to specifically detect small (<1 cm) metastatic lesions in the liver. The early detection of number and location of metastatic lesions is critical. There is also a need to characterise and specifically identify the origin of the tumour with no interference from other possible lesions (e.g. cysts, benign lesions, non-treatable tumours).
A low-molecular weight heat-stable toxin is produced by enterotoxic strains of E. coli. This toxin, known as ST peptide, mediates acute diarrheal disease by binding to its receptor on colorectal cells and stimulating guanylate cyclase. Synthetic ST peptides that bind to the ST receptor without mediating acute diarrheal disease are disclosed in U.S. Pat. Nos. 4,545,931 and 4,886,663. These synthetically produced peptides are suitable for human administration for therapeutic and diagnostic purposes.
Targeted ligands directed towards receptors that are expressed selectively on tumour cells of colorectal origin are a means to specifically detect the presence of cancers of colorectal origin. Thus, the ST receptor is a potential target mechanism. Gastrointestinal mucosal cells specifically express the ST receptor and the expression persists after colonic and rectal mucosal cells undergo malignant neoplasic transformation. No ST peptide has been found in any other extra-intestinal tissues, therefore specificity of ligands to tissue of gastrointestinal origin is maintained. Similar levels of expression have been found in human primary and metastatic colorectal tissues with different grades of differentiation and location. A specific ligand for the ST receptor will only bind to metastatic disease, as access to the apical side of intestinal cells will be avoided if the compound is injected intravenously.
Radiolabelled ST peptides for CRC imaging and diagnosis have been previously documented. U.S. Pat. No. 5,518,888 claims radiodiagnostic agents based on ST peptides. In one embodiment of that invention, the peptides may be linked to a radioactive imaging agent, such as radioactive iodine, 111In or 99mTc. 99mTc is chelated by DTPA, which is converted to an anhydride and reacted with an ST peptide. No other chelates are disclosed in U.S. Pat. No. 5,518,888. Radiolabelling thus renders the peptides suitable for use in radioimaging metastasized colorectal cancers. U.S. Pat. No. 6,060,037 discloses a method of radioimaging metastatic CRC using such radiolabelled ST peptides. The detection of localised accumulation or aggregation of radioactivity following administration of radiolabelled ST peptide is indicative of the presence of cells with ST receptors. WO 99/21587 and WO 99/39748 also disclose radiolabelled ST peptides for diagnostic imaging. In WO 99/21587 the preferred classes of radiometal complexing agents are terpyridines and phenanthrolines. In WO 99/39748 the complexing agents comprise a macrocyclic oligo-2,6-pyridine-containing ring which is a derivative of a terpyridine, quaterpyridine, quinpyridine, or sexipyridine.